The present invention relates to a cyclodextrin inclusion compound with hinokitiol and provides a novel and convenient method for preparing this inclusion compound.
Hinokitiol is a 7-membered ring compound which is contained in an acidic oil derived from certain kinds of perennial plant: it may also be synthesized by well-known routes. It was first described as one of the components of an extract from the heart wood of trees of the species Thuja plicata and named .beta.-thujaplicin [see. for example. H. Erdtman et al., Nature 161, 719 (1948), H. Erdtman et al., Acta Chem. Scand. 2, 625 (1948) and H. MacLean et al., Anal. Chem. 28, 509 (1956)] but this was subsequently identified with an extract from the heart wood of the Japanese hinoki (Chamaecyparis obtusa) which had been named hinokitiol [T. Nozoe, Bull. Chem. Soc. Japan 11, 295 (1936)] and the material is now commonly termed "hinokitiol" although in older literature the term ".beta.-thujaplicin" may be used.
Hinokitiol has strong bactericidal and bacteriostatic activity and has been used medically and in foods, particularly for the preservation of fresh fish. Its use for preventing the discoloration of animal and plant products is described in Japanese patent application Ser. No. 195819/82 and its use as a food preservative is described in Japanese patent application Ser. No. 98976/83.
However, hinokitiol has extremely limited solubility in water; even at a temperature of 25.degree. C. its solubility is only about 0.12%; at the temperature commonly used for preserving fresh fish, which is generally the temperature of an ice-water mixture. i.e. between 0.degree. and 5.degree. C., its solubility is so low as to be insignificant. Hinokitiol is an acidic substance and can, therefore, be converted to alkali metal salts, which do have improved water solubility. However, the use of such alkali metal salts is prohibited in Japan by food health legislation. Common organic solvents in which hinokitiol is soluble cannot be used in the preservation of fish for many reasons: e.g. they may be harmful to health, they may be unacceptable by virtue of their taste or smell or they may harm the texture or flavour of the fish.
Moreover, hinokitiol has a very strong and pronounced odor, which has very seriously limited its use as a food preservative. It would clearly be desirable to provide a composition retaining the desirable properties of hinokitiol but free from this undesirable odor.
There is, therefore, a need for a method of solubilizing hinokitiol by means which will comply with existing legislation, will not give rise to any health hazards or potential health hazards and will not have any adverse effects on fish, the latter becoming of increasing importance as enjoyment of raw fish, such as sushi and sashimi, spreads to Western countries.
We have now discovered that these aims can be achieved by forming an inclusion compound of hinokitiol within cyclodextrin. Surprisingly, as well as having improved solubility, this inclusion compound is free from the strong odor of hinokitiol and can, therefore, be used for the preservation of a wide range of foodstuffs.
Cyclodextrin is a well-known clathrate and it is known that certain compounds of limited water solubility can be made more water-soluble by formation of a cyclodextrin inclusion compound, as described, for example, in: "Inclusion Compounds" by Watabe, Chihara, Iwanami Gendai Kagaku Koza, 1956; "Inclusion Compounds and Their Applications" by Seki, Latest Chemistry and its Application, Maki Bookstore, 1958; "History of Development of Inclusion Compounds" by Kanaba, Realm of Chemistry, Nankodo, 1961; and K. Vekama et al., Chem. Pharm. Bull., 27(2), 398 (1979).
Various processes have been proposed for producing inclusion compounds of substances having limited water solubility within cyclodextrin. For example, where the substance of limited water solubility is a liquid, the substance may be added to an aqueous solution of cyclodextrin and then the resulting mixture stirred, until the inclusion compound is precipitated; the precipitate may then be collected by conventional means. Where the substance of limited water solubility is a solid, one suitable method comprises dissolving the substance in a suitable solvent (for example an ether such as diethyl ether), adding the solution to an aqueous solution of cyclodextrin, shaking and/or stirring the mixture sufficiently until a precipitate of the inclusion compound is formed and then collecting the precipitate. Various other methods are known, for example the "kneading method". In this method, the substance in question is added to a slurry of .beta.-cyclodextrin and the mixture is kneaded until homogeneous, whereupon water is added to separate the inclusion compound. Hinokitiol, however, is so insoluble in water that this method cannot, in practice, be used.
Recently, in Japanese patent Publication No. 35968/83, there has been proposed a process for collecting an inclusion compound by freeze-drying a mixture. However, the cost of installation and running of a freeze-drying plant is too great for its use to be an economic proposition for the preparation of a relatively low value-added product such as a hinokitiol composition. Accordingly, none of these known processes has been found to be particularly satisfactory for manufacturing a cyclodextrin inclusion compound of hinokitiol for use in food processing.